3-O-Sulfation induces sequence-specific compact topologies in heparan sulfate that encode a dynamic sulfation code.

Area of Science:

• Biochemistry
• Glycobiology
• Structural Biology

Background:

• Heparan sulfate (HS) is a highly diverse biopolymer known to modulate numerous proteins.
• HS exhibits significant configurational and conformational diversity, primarily through sulfation patterns and iduronic acid puckering.
• The canonical topology of HS is considered a linear helical rod.

Purpose of the Study:

• To investigate whether rare 3-O-sulfation in HS can induce novel topologies.
• To explore the potential of these novel topologies in selective protein recognition.

Main Methods:

• Molecular dynamics (MD) simulations were employed to study a library of 24 distinct HS hexasaccharides.
• Analysis focused on identifying conformational changes and topological variations, particularly in response to 3-O-sulfation.

Main Results:

• Novel compact (C) topologies were discovered, significantly populated by 3-O-sulfated HS sequences containing iduronic acid (IdoA) residues.
• Sequences with glucuronic acid (GlcA) or lacking 3-O-sulfate groups predominantly adopted the canonical linear (L) topology.
• The L to C topology transition is driven by dynamics around IdoA → GlcN glycosidic linkages, reducing charge repulsion and optimizing water and cation interactions.

Conclusions:

• 3-O-sulfation is a key determinant in generating unique, sequence-specific compact HS topologies.
• These novel topologies suggest that HS encodes a dynamic sulfation code for selective protein binding.
• The findings open new avenues for exploiting HS structure in targeted therapeutic strategies.